Inflammation in peripheral tissues is implicated as a key mediator of insulin resistance and other metabolic consequences of obesity. Recent studies show that a similar inflammatory process also occurs in the hypothalamus, and that this process, unlike inflammation in peripheral tissues, is a potential cause (and not just a consequence) of obesity and associated metabolic impairment. These effects of hypothalamic inflammation are mediated in part via impaired neuronal responses to the hormones insulin and leptin, key signals in the central control of both energy homeostasis and insulin sensitivity. Our novel findings that hypothalamic proinflammatory cytokine expression occurs within just 24 h of the onset of high-fat (HF) feeding, an effect that coincides with a marked increase of caloric intake, and that both parameters are gradually return to normal over the subsequent week suggest a link between neuronal inflammatory responses and the hyperphagic response to a HF diet. Coincident with these early responses, microglia (the macrophage of the brain) accumulate in the arcuate nucleus (ARC, a key hypothalamic area for sensing input from insulin and leptin) - but not other brain areas. These and other observations strongly suggest that interactions between hypothalamic neurons and microglia are determinants of weight gain during HF feeding. Further, acute reversal of hypothalamic inflammation fully reverses systemic insulin resistance induced by 3 wk of HF feeding. Here, we propose studies to determine the time course over which hypothalamic microglia and neurons respond to HF feeding, and whether the response of microglia, neurons, or both cell types is required for this inflammation. We will also identify mechanisms underlying microglial accumulation in the ARC during HF feeding, and determine whether disruption of this microglial response predisposes to obesity. Lastly, we will investigate the mechanism whereby hypothalamic inflammatory signaling induced by HF feeding causes insulin resistance. These studies will clarify how interactions between hypothalamic neurons and microglia influence weight gain and metabolic impairment induced by HF feeding, which will inform our understanding of the pathogenesis of both obesity and insulin resistance and facilitate the discovery of new approaches to the treatment and prevention of these disorders. PUBLIC HEALTH RELEVANCE: This proposal focuses on mechanisms whereby high-fat feeding causes obesity and insulin resistance, both of which are major public health problems worldwide. Growing evidence implicates inflammation in peripheral tissues as a major cause of insulin resistance and other metabolic consequences of obesity. During high-fat feeding, inflammation also occurs in the hypothalamus, a key brain area for the control of both body weight and glucose metabolism. Unlike inflammation in peripheral tissues, hypothalamic inflammation is implicated as a cause (and not just a consequence) of both obesity and insulin resistance. By clarifying the mechanisms underlying these effects of hypothalamic inflammation, our studies will advance our understanding of obesity pathogenesis and its links to metabolic dysfunction, and identify new potential targets for the treatment of these conditions.